ERIN O'SHEA INVESTIGATES HOW CELLS RESPOND TO THEIR SURROUNDINGS

by
Charlie Schmidt

October 24th, 2005

Erin O'Shea

Shortly after finishing her freshman year at Smith College, Erin O’Shea made a fateful decision: Instead of spending the summer at home in upstate New York, mowing lawns and painting houses for her family’s contracting business, she would stay on campus and work in a chemistry lab. In retrospect, this was a good move—the research experience was personally transforming, O’Shea says, and catalyzed an outstanding scientific career that has since led to international recognition and acclaim. At the age of just 39, O’Shea is already a member of the National Academy of Sciences, a winner of many prestigious awards, and a leading figure in gene regulation research. In August, she became an MCB professor and co-Director of Harvard’s Bauer Center for Genomics Research, which she will lead along with Andrew Murray, the current MCB Department Chairman.

O’Shea’s research is motivated by her desire to understand how cells interpret and respond to their environments. "This is fundamental to the life of the cell," she explains. "The whole manner by which cells detect and respond to their environment is relevant to so many basic and applied questions. Most cancers, for instance, emerge when that process goes awry." Today, O’Shea’s work combines studies of signal transduction, proteomics, and information processing in transcriptional regulatory networks, all of which contribute to the cell’s environmental interactions. "We know a lot about the parts that cells use in sensing but very little about how responses are coordinated," she says. "What I really want to do is find out how these parts work together to generate complex behaviors."

Sitting on a Park Bench

After finishing her bachelor’s in biochemistry in 1988, O’Shea planned to attend medical school at Yale. But Peter Kim, an MIT Professor and Whitehead Fellow, for whom O’Shea was working during the summer, encouraged her to join his laboratory to pursue a PhD, which O’Shea completed in an astonishing two and half years. "I was lucky," O’Shea modestly says of her doctoral experience. "I was at the right place, at the right time, with a great advisor, in a great lab."

O’Shea chose her thesis topic while sitting on a park bench behind the Whitehead Institute. She was reading a paper in Science about the leucine zipper—a proposed model for sequences that many transcription factors share in common. The paper’s authors had proposed that leucine residues within these sequences fold into alpha helical pairs that interdigitate like a zipper’s teeth. But as she read the paper, O’Shea began to suspect otherwise, imagining that the leucine zipper in these transcription factors might actually be a "coiled-coil," which is a structure more akin to that of keratin and other well-characterized proteins. Kim’s laboratory had the needed equipment to test this hypothesis, which O’Shea set out to do. First, she made synthetic peptides corresponding to leucine zipper regions in several key transcription factors, including Fos, Jun, and Gcn4 in yeast. Then, she used a variety of analytical techniques to visualize how these synthetic structures were organized. Her research ultimately proved the leucine zippers formed alpha helices that were oriented in a parallel configuration consistent with a coiled-coil, thus confirming her intuition. O’Shea went on to solve the crystal structure of the Gcn4 leucine zipper, and with these discoveries, cemented her reputation in structural biology.

Signal Transduction in the PHO Pathway

Upon graduating from MIT, O’Shea accepted a faculty position at the University of California at San Francisco. But first—with UCSF’s blessing—she spent 2 years working with Robert Tijan at Berkeley and UCSF Professor Ira Herskowitz on a problem that still fuels some of her research now. O’Shea was interested in how chromatin structure influences gene expression. DNA in eukaryotic cells is bound to histone proteins, which help compact it to fit into the space of the nucleus. Working with yeast cells, O’Shea tried to figure out how transcription factors penetrate chromatin and gain access to DNA, to initiate gene expression. The research eventually led her to a gene called PHO5, which has chromatin that must be rearranged for transcription to occur. O’Shea spent months studying the regulation of this gene, trying to uncover how the chromatin was changed so that transcription factors could bind to the DNA. But the task proved excessively challenging, so she began to study how transcription of the PHO5 gene is modulated by environmental changes in the level of phosphate, a cell nutrient.

O’Shea still uses the PHO pathway as a model system for studies of signal transduction today. "That’s really what I’m best known for," she says. "We’ve figured out some very interesting things about the signaling pathway, and how phosphorylation regulates the activity of this factor and other processes in cell biology, like the factor’s movement into and out of the nucleus."

Proteomic Research

In 2000, while still at UCSF, O’Shea was funded by the Howard Hughes Medical Institute to pursue non-traditional research. "HHMI challenged us to do something new, it could be whatever I wanted, but it had to be good," she recalls. What she ultimately decided to do was create a system for monitoring all the proteins in the budding yeast cell. Her partner in this endeavor was Jonathan Weissman, also at UCSF, with whom she still collaborates today. The approach entails creating 6,000 separate yeast strains, each expressing a single tagged protein, which is itself detectable by a given reagent. Using this technology, O’Shea and her colleagues have been able to quantify the lifespans, abundance, and localization of proteins, in addition to many other changes that occur in response to environmental conditions. A similar approach for use in human cells is still a long ways off, O’Shea admits. But once developed, such a technology could fuel dramatic biomedical advances. "It would have a huge impact," she predicts. "The ability to measure all the proteins in a human cell in an unbiased way might allow you to detect human cancers early on. It would impact on drug discovery and our understanding of how drugs work. Today, scientists use gene and RNA measurements as proxies for proteins, but the bottom line is that proteins, not RNA, carry out most functions in cells. So, there are many interesting biological questions you could answer if you could look at all the proteins directly."

Information Processing in Transcriptional Regulatory Networks

In another fascinating dimension to her research, O’Shea investigates how unique environmental stressors simultaneously influence the expression of hundreds of genes. She has focused particularly on Hog1, a kinase that somehow modulates up to 500 genes at once, each expressed at varying levels to create a remarkably complex response. Andrew Capaldi, a postdoctoral fellow in O’Shea’s lab, has found that Hog1 controls the activity of multiple transcription factors, which in turn activate subsets of genes according to their own binding patterns. Her efforts to map the architecture of the response network are aided by collaborations with bioinformatic specialists, namely Aviv Regev from Harvard and Nir Friedman from Hebrew University. "We do the lab research and they do the computation," O’Shea says. "Eukaryotic gene expression is a great problem and it’s fun to interact with these people who have different backgrounds."

Contemplating opportunities from the wide expanse of her new office at the Bauer Center, O’Shea says the decision to come to Harvard was easy to make. "There are huge benefits to being at a research university complete with other science faculties like chemistry, physics, engineering and math. I’m already working with people from other disciplines and I hope to attract more—they bring a new perspective to the lab and the problems we work on."

The other key attraction, O’Shea adds, concerns the opportunity for more involvement in undergraduate teaching and education. Attributing her own success in part to those who inspired her early on, O’Shea says she’d like to have an equally positive influence on young students herself. "I’ve always thought that’s an important part of what it means to be a professor," she says. "It’s not just about teaching graduate or medical students. All in all, I’m excited to be here, I think it's going to be great. Teaching, research, everything. I’m busy!"